A number of compounds structurally related to the compounds of the invention are known from the prior art.
So, EP patents Nos. 0 138 280 and 0 185 429 disclose an extremely broad class of piperazinyl compounds having a bicyclic hetero aryl radical in the 4-position and a heteroaryl-, aryl- or alkyl substituted carbamoylethyl or carbamoylpropyl group in the 1-position. Said compounds are alleged to show blood pressure lowering effect through a central mechanism. EP 0 372 657 discloses similar derivatives differing only in that they have slightly different substituents on the bicyclic heteroaryl radical. These latter derivatives are said to exert anxiolytic effects in animal models without showing effect on the blood pressure. One of the compounds covered by EP patent No. 0 138 280, i.e. the compound 4-fluoro-N-[2-(4-(2-hydroxymethyl-1,4-benzodioxan-5-yl)piperazine-1-yl)eth yl]benzamide, which is known as flesinoxan has recently been reported to be a high efficacy 5-HT.sub.1A agonist having antidepressant and anxiolytic effects (Schipper et al, Human Psychopharm., 1991, 6, S53).
EP patent No 0 364 327 discloses a class of 4-[2-(4-(naphthyl- or isoquinolyl)piperazine-1-yl)ethyl]-2-quinolone derivatives having 5-HT.sub.1A and 5-HT.sub.2 receptor activity. The compounds are said to be agonists, partial agonists or antagonists in vivo. EP 0 343 050 describes a group of 6-phenyl-3-[(4-(naphthyl or isoquinolyl)piperazine-1-yl)alkyl(2-4)]-1H,3H-pyrimidine-2,4-dione compounds said to posses 5-HT.sub.1A and 5-HT.sub.2 receptor activity. Again, with respect to the 5-HT.sub.1A receptor, the compounds are said to be agonists, partial agonists or antagonists in vivo.
In International patent publication No. WO 92/03426 a class of piperazine derivatives having naphtyl or quinolyl in the 4-position and a N-aryl substituted carbamoyl alkyl group or a N-aryl substituted ureido alkyl group in the 1-position is described. Said compounds are claimed to exhibit affinity for various receptors, including 5-HT.sub.2, 5-HT.sub.1A, alpha and dopamine receptors.
EP patent No 0 466 585 relates to 1-(benzamidoalkyl)-4-(naphthyl- or quinolyl)piperidines or -tetrahydropyridines having 5-HT.sub.1A receptor affinity and found to exhibit potent antihypertensive effect in animals.
Finally, EP 0 490 772 A1 discloses a class of 1,4-disubstituted piperazine derivatives alleged to show 5-HT.sub.1A antagonistic activitivities. Said derivatives have a 5-benzodioxanyl or 7-isobenzofuranyl radical in the 4-position and a lower alkyl chain substituted with a bicyclic carbo ring system in the 1-position.
Compounds having central serotonergic 5-HT.sub.1A activity may according to well known and recognized pharmacological principles be devided into full agonists, partial agonists and antagonists.
Clinical studies of known 5-HT.sub.1A partial agonists such as e.g. buspirone (8-[4-[4-(2-pyrimidyl)-1-piperazinyl]butyl]-8-azaspiro[4,5]decane-7,9-dion e), ipsapirone (4,4-dimethyl-1-[4-[4-(2-pyrimidyl)-1-piperazinyl]butyl]-2,6-piperidinedio ne), and gepirone (2-[4-[4-(2-pyrimidyl)-1-piperazinyl]butyl]-1,2-benzothiazol-3(2H)-one-1,1 -dioxide), have shown that 5-HT.sub.1A partial agonists are useful in the treatment of anxiety disorders such as generalised anxiety disorder, panic disorder, and obsessive compulsive disorder (Glitz, D. A., Pohl, R., Drugs 1991, 41, 11). Preclinical studies indicate that full agonists also are useful in the treatment of the above mentioned anxiety related disorders (Schipper, Human Psychopharm., 1991, 6, S53).
There is also evidence, both clinical and preclinical, in support of the beneficial effect of 5-HT.sub.1A partial agonists in the treatment of depression as well as impulse control disorders and alcohol abuse (van Hest, Psychopharm., 1992, 107, 474; Schipper et al, Human Psychopharm., 1991, 6, S53; Cervo et al, Eur. J. Pharm., 1988, 158, 53; Glitz, D. A., Pohl, R., Drugs 1991, 41, 11).
5-HT.sub.1A agonists and partial agonists inhibit isolation-induced aggresion in male mice indicating that these compounds are useful in the treatment of aggression (Sanchez et al, Psychopharmacology, 1993, 110, 53-59).
Furthermore, recent studies also indicate that 5-HT.sub.1A receptors are important in the serotonergic modulation of haloperidol-induced catalepsy (Hicks, Life Science 1990, 47, 1609) suggesting that 5-HT.sub.1A agonists are useful in the treatment of the side effects induced by conventional antipsychotic agents such as e.g. haloperidol.
5-HT.sub.1A agonists have shown neuroprotective properties in rodent models of focal and global cerebral ischaemia and may, therefore, be useful in the treatment of ischaemic disease states (Prehn, Eur. J. Pharm. 1991, 203, 213).
Pharmacological studies have been presented which indicates that 5-HT.sub.1A antagonists arm useful in the treatment of senile dementia (Bowen et al, Trends Neur. Sci. 1992, 15, 84).
Both in animal models and in clinical trials it has been shown that 5-HT.sub.1A agonists exert antihypertensive effects via a central mechanism (Saxena and Villalaon, Trends Pharm. Sci. 1990, 11, 95; Gillis et al, J. Pharm. Exp. Ther. 1989, 248, 851. 5-HT.sub.1A ligands may, therefore, be beneficial in the treatment of cardiovascular disorders.
Accordingly, agents acting on the 5-H.sub.1A receptor, both agonists and antagonists, are believed to be of potential use in the therapy of such conditions and thus being highly desired.
It has now been found that compounds of a certain class of fused benzoderivatives bind to the 5-HT.sub.1A receptor with high affinities. Furthermore, it has been found that the compounds cover a broad range of selectivities for the 5-HT.sub.1A receptor vs. the dopamine D.sub.2 receptor and the alpha.sub.1 adrenoceptor and a broad range of the efficacy scale.